靶向SHP2的变构抑制剂和PROTAC药物研究进展  

Progress on Allosteric Inhibitors Targeting SHP2 and PROTAC Drugs

作　　者：姜蒙蒙 李晓博 周丽莹 董磊 JIANG Mengmeng;LI Xiaobo;ZHOU Liying;DONG Lei(Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment(Ministry of Industry and Information Technology),Aerospace Center Hospital,School of Life Science,Beijing Institute of Technology,Beijing 100081,China;Beijing Tide Pharmaceutical Co.,Ltd,Beijing 100176,China)

机构地区：[1]北京理工大学生命学院、航天中心医院、分子医学和生物诊疗工信部重点实验室,北京100081 [2]北京泰德制药股份有限公司,北京100176

出　　处：《中国生物工程杂志》2024年第11期66-75,共10页China Biotechnology

基　　金：国家自然科学基金(U21A20200)资助项目。

摘　　要：含Src同源2结构域蛋白酪氨酸磷酸酶(SHP2)作为第一个蛋白酪氨酸磷酸酶(protein tyrosine phosphatase, PTP)家族被证实的原癌蛋白,具有调节多种信号通路的能力,包括RAS-RAF-ERK、PI3K-AKT和JAK-STAT等,是抗肿瘤药物研究的重要靶点。SHP2在促进肿瘤细胞耐药及调节肿瘤微环境中的免疫细胞功能方面也发挥着重要作用。变构抑制剂的发现推动了SHP2药物的研发进程,已有多个变构抑制剂药物正在进行单药或联合用药临床试验。与此同时,蛋白质水解靶向嵌合体(proteolysis targeting chimeras, PROTACs)作为一种新型药物设计方式,被广泛应用于靶向SHP2的药物开发中。总结靶向SHP2的变构抑制剂的临床研究结果,梳理PROTAC-SHP2药物研发进展,以期为SHP2药物分子的设计及改进提供启发。The protein tyrosine phosphatase containing Src homology 2(SH2)domain(SHP2)is the first oncogenic protein confirmed belong to the protein tyrosine phosphatase(PTP)family.It has the potential to regulate multiple signaling pathways,including RAS-RAF-ERK,PI3K-AKT,and JAK-STAT,making it an important target for anti-tumor drug discovery.SHP2 also plays a critical role in promoting tumor cell resistance and modulating immune cell function in the tumor microenvironment.The discovery of allosteric inhibitors has advanced the development of SHP2 drugs,with several allosteric inhibitor drugs currently in clinical trials as monotherapy or combination therapy.At the same time,proteolysis targeting chimeras(PROTACs),a novel drug design approach,are being widely used in the development of SHP2-targeting drugs.This article summarizes the clinical research results of allosteric inhibitors targeting SHP2,and outlines the progress of PROTAC-SHP2 drug development,with the aim of providing inspiration for the design and improvement of SHP2 drug molecules.

关 键 词：蛋白酪氨酸磷酸酶2(SHP2) 变构抑制剂 蛋白质水解靶向嵌合体 

分 类 号：Q814[生物学—生物工程]